Skip to main content

Main menu

  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SUBSCRIBE

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Journal of Neuroscience
  • Log in
  • My Cart
Journal of Neuroscience

Advanced Search

Submit a Manuscript
  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SUBSCRIBE
PreviousNext
Journal Club

A Repulsive Environment Induces Neurodegeneration of Midbrain Dopaminergic Neurons

Angel J. Santiago-Lopez
Journal of Neuroscience 7 February 2018, 38 (6) 1323-1325; DOI: https://doi.org/10.1523/JNEUROSCI.3070-17.2017
Angel J. Santiago-Lopez
Interdisciplinary Bioengineering Graduate Program and School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Angel J. Santiago-Lopez
  • Article
  • Info & Metrics
  • eLetters
  • PDF
Loading

The motor impairments in Parkinson's disease (PD) are caused mainly by the progressive loss of dopaminergic neurons in the substantia nigra par compacta (SNpc). The SNpc extends axons to the dorsal striatum, forming the nigrostriatal pathway, which is involved in motor function. In PD, degeneration of these axons and the consequent loss of dopaminergic input to the striatum alter activity patterns in basal ganglia circuits. This loss precedes motor symptoms (Cheng et al., 2010; Dijkstra et al., 2015; Tagliaferro and Burke, 2016). Although pharmacological dopamine replacement therapy remains the standard treatment for PD, it does not prevent progression of the disease. Efforts to halt this progression have instead focused on targets, such as protein misfolding and aggregation, oxidative stress-induced apoptosis, and neuroinflammation.

Recently, axon guidance molecules have emerged as potential contributors to neurodegeneration in several conditions, including PD (Van Battum et al., 2015). One such molecule is repulsive guidance molecule a (RGMa), a cell-membrane-associated glycosylphosphatidylinositol-anchored glycoprotein that interacts with its receptor neogenenin to mediate repulsive axonal guidance and regulate neuron survival (Matsunaga et al., 2004; Itokazu et al., 2012). In previous work, transcriptional profiling revealed that RGMa levels were twofold higher in the SNpc of PD patients than in controls (Bossers et al., 2009). In a recent study published in The Journal of Neuroscience, in situ hybridization analysis of SN tissue from PD patients and age-matched controls revealed that RGMa expression was restricted to dopaminergic neurons (Korecka et al., 2017). These results motivated the authors to further investigate the role of RGMa with respect to dopaminergic neurons in the nigrostriatal pathway.

To elucidate whether overexpression of RGMa in the SN alone could induce PD-like neurodegeneration, Korecka et al. (2017) injected adeno-associated viral vectors (AAVs) encoding mouse RGMa under the control of the human synapsin-1 promoter (AAV-RGMa) into the SN of mice. Intranigral administration of AAV-RGMa resulted in RGMa expression in both the SN and the striatum, which is consistent with an anterograde transport of RGMa along nigrostriatal projections. AAV-RGMa overexpression reduced the number of tyrosine hydroxylase-expressing (TH+), presumably dopaminergic, neurons in the SNpc by 38%–40% and induced significant motor impairments over the subsequent ∼19 weeks. Importantly, numbers of non-TH+ neurons remained unaltered after AAV-RGMa administration, suggesting that the effect was specific to dopaminergic neurons. Moreover, the effects were comparable with those produced in rodent models of PD involving injection of the dopamine-neuron-specific neurotoxin 6-hydroxydopamine or viral delivery of PD-linked mutant α-synuclein (Alvarez-fischer et al., 2008; Ip et al., 2017).

Interestingly, when AAV-RGMa was injected bilaterally, the decrease in the number of TH+ neurons was accompanied by an increase in TH expression in the remaining neurons. While an increase in TH expression following an insult might be indicative of a compensatory mechanism, it does not necessarily translate into the restoration of dopamine signaling along the nigrostriatal pathway. Indeed, the authors detected no such compensatory increase in TH expression in the striatum after high-dose AAV-RGMa administration (Korecka et al., 2017, their Fig. 6B–E), supporting the hypothesis that loss of striatal dopamine underlies the observed motor deficits. In face of these results, one can hypothesize that overexpression of RGMa leads to a “dieback” or retrograde axonal degeneration, which prevents any compensatory mechanism from countering disease progression. This would be consistent with the observed increase in levels of RGMa in the striatum after the administration of both high- and low-titer dosages of AAV-RGMa because this RGMa could act locally to induce axon retraction.

Korecka et al. (2017) also sought to address the role of RGMa in neuroinflammation, a strong component of the pathophysiology of PD. Reactive gliosis, as identified by levels of the ionizing calcium-binding adaptor molecule 1 (expressed in reactive microglia) and GFAP (expressed in reactive astrocytes), was significantly increased in the SNpc after both high- and low-titer AVV-RGMa injections compared with injection of control vectors. The glial response elicited by RGMa overexpression is notable because it suggests that RGMa might induce neurodegeneration through glial activation in addition to retraction of striatal terminals.

Whether neuroinflammation is a causative factor in PD or only aggravates neurodegeneration in response to cell-autonomous factors (e.g., protein homeostasis dysregulation, mitochondrial dysfunction) is an unresolved question. In the work of Korecka et al. (2017), it is unlikely that the observed neuroinflammatory response is the main mechanism driving dopaminergic neurodegeneration because high- and low-titer AAV-RGMa elicited comparable increases in ionizing calcium-binding adaptor molecule 1 and GFAP expression but produced different degrees of motor impairment. Therefore, the results suggest that the glial response is secondary to neuronal dysfunction caused by RGMa overexpression. Future work should address whether exposure to proinflammatory cytokines (e.g., interleukin-1) increases the susceptibility of dopaminergic neurons to RGMa-induced neurodegeneration, as is observed in an LPS-primed 6-hydroxydopamine rat model of PD (Koprich et al., 2008).

The molecular mechanisms by which RGMa promotes neurodegeneration remain unclear. Previous work points to a mechanism in which the prosurvival protein kinase Akt is dephosphorylated in response to RGMa-neogenin binding (Tanabe and Yamashita, 2014). Moreover, evidence from postmortem analysis of brain tissue from PD patients supports the notion that dephosphorylation of Akt is present in PD-like neurodegeneration (Malagelada et al., 2008). Korecka et al. (2017) evaluated the levels of phosphorylated Akt but did not identify significant differences between AAV-RGMa and control-injected animals. Other pathways, however, might be involved in RGMa-induced neurodegeneration. For instance, other known inhibitory factors in the CNS, such as ephrins, Nogo-A, and chondroitin sulfate proteoglycans, converge on the RhoA/ROCK signaling pathway to induce axonal degeneration. RGMa might therefore be acting through this pathway to induce neuropathological changes. Indeed, there is evidence that RGMa induces growth cone collapse and neurite retraction via RhoA GTPase activation (Conrad et al., 2007). The precise mechanism of RGMa-induced RhoA activation involves the recruitment of the RGMa coreceptor Unc5, which associates with the leukemia-associated Rho guanine nucleotide exchange factor to induce RhoA activation and growth cone collapse (Hata et al., 2009). Moreover, RhoA activation has been linked to neuronal apoptosis (Dubreuil et al., 2003; Semenova et al., 2007), and its inhibition has been shown to improve neuron survival and regeneration in vivo (Koch et al., 2014). Thus, it is possible that RGMa overexpression in SN triggers a signaling cascade orchestrated by active RhoA that affects both dopaminergic neuron survival and the integrity of striatal axon terminals.

The identification of potential mechanisms by which RGMa drives dopaminergic cell loss could translate into effective therapeutic interventions in two ways. First, it could lead to enhanced cell-replacement therapies if modulation of RGMa-neogenin signaling facilitates the survival and growth of neural grafts in the PD brain. Second, biotherapeutics (e.g., gene therapy, antibody-directed therapy) modulating RGMa expression could provide neuroprotection in early stages of PD. Consistent with this therapeutic strategy, antibody-mediated inhibition of RGMa has been shown to be neuroprotective in models of stroke (Tassew et al., 2014) and spinal cord injury (Mothe et al., 2017). It will also be valuable to consider the interplay between repulsive axonal guidance molecules, such as RGMa, and other major neuropathological factors contributing to the inhibitory milieu of the PD brain, such as intracellular inclusions containing α-synuclein, to further understand the neuropathology of PD and thus identify novel therapeutic targets.

Footnotes

  • Editor's Note: These short reviews of recent JNeurosci articles, written exclusively by students or postdoctoral fellows, summarize the important findings of the paper and provide additional insight and commentary. If the authors of the highlighted article have written a response to the Journal Club, the response can be found by viewing the Journal Club at www.jneurosci.org. For more information on the format, review process, and purpose of Journal Club articles, please see http://jneurosci.org/content/preparing-manuscript#journalclub.

  • This work was supported in part by the National Science Foundation Graduate Research Fellowship DGE-1650044. A.J.S.-L. thanks Dr. Robert E. Gross and Dr. Claire-Anne Gutekunst for their ongoing support and guidance.

  • The authors declare no competing financial interests.

  • Correspondence should be addressed to Angel J. Santiago-Lopez, Emory University Department of Neurosurgery, Woodruff Memorial Research Building, 101 Woodruff Circle, Suite 6337, Atlanta, GA 30322. angel.stgolopez{at}gatech.edu

References

  1. ↵
    1. Alvarez-fischer D,
    2. Henze C,
    3. Strenzke C,
    4. Westrich J,
    5. Ferger B,
    6. Höglinger GU,
    7. Oertel WH,
    8. Hartmann A
    (2008) Characterization of the striatal 6-OHDA model of Parkinson's disease in wild type and α-synuclein-deleted mice. Exp Neurol 210:182–193. doi:10.1155/2015/313702 pmid:PMC4437346
    OpenUrlCrossRefPubMed
  2. ↵
    1. Bossers K,
    2. Meerhoff G,
    3. Balesar R,
    4. van Dongen JW,
    5. Kruse CG,
    6. Swaab DF,
    7. Verhaagen J
    (2009) Analysis of gene expression in Parkinson's disease: possible involvement of neurotrophic support and axon guidance in dopaminergic cell death. Brain Pathol 19:91–107. doi:10.1111/j.1750-3639.2008.00171.x pmid:18462474
    OpenUrlCrossRefPubMed
  3. ↵
    1. Cheng HC,
    2. Ulane CM,
    3. Burke RE
    (2010) Clinical progression in Parkinson disease and the neurobiology of axons. Ann Neurol 67:715–725. doi:10.1002/ana.21995 pmid:20517933
    OpenUrlCrossRefPubMed
  4. ↵
    1. Conrad S,
    2. Genth H,
    3. Hofmann F,
    4. Just I,
    5. Skutella T
    (2007) Neogenin-RGMa signaling at the growth cone is bone morphogenetic protein-independent and involves RhoA, ROCK, and PKC. J Biol Chem 282:16423–16433. doi:10.1074/jbc.M610901200 pmid:17389603
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Dijkstra AA,
    2. Ingrassia A,
    3. de Menezes RX,
    4. van Kesteren RE,
    5. Rozemuller AJ,
    6. Heutink P,
    7. van de Berg WD
    (2015) Evidence for immune response, axonal dysfunction and reduced endocytosis in the substantia nigra in early stage Parkinson's disease. PLoS One 10:e0128651. doi:10.1371/journal.pone.0128651 pmid:26087293
    OpenUrlCrossRefPubMed
  6. ↵
    1. Dubreuil CI,
    2. Winton MJ,
    3. McKerracher L
    (2003) Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system. J Cell Biol 162:233–243. doi:10.1083/jcb.200301080 pmid:12860969
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Hata K,
    2. Kaibuchi K,
    3. Inagaki S,
    4. Yamashita T
    (2009) Unc5B associates with LARG to mediate the action of repulsive guidance molecule. J Cell Biol 184:737–750. doi:10.1083/jcb.200807029 pmid:19273616
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Ip CW,
    2. Klaus L-C,
    3. Karikari AA,
    4. Visanji NP,
    5. Brotchie JM,
    6. Lang AE,
    7. Volkmann J,
    8. Koprich JB
    (2017) AAV1/2-induced overexpression of A53T-α-synuclein in the substantia nigra results in degeneration of the nigrostriatal system with Lewy-like pathology and motor impairment: a new mouse model for Parkinson's disease. Acta Neuropathol Commun 5:11. doi:10.1186/s40478-017-0416-x pmid:PMC5286802
    OpenUrlCrossRefPubMed
  9. ↵
    1. Itokazu T,
    2. Fujita Y,
    3. Takahashi R,
    4. Yamashita T
    (2012) Identification of the neogenin-binding site on the repulsive guidance molecule A. PLoS One 7:1–6. doi:10.1371/journal.pone.0032791 pmid:22396795
    OpenUrlCrossRefPubMed
  10. ↵
    1. Koch JC,
    2. Tönges L,
    3. Michel U,
    4. Bähr M,
    5. Lingor P
    (2014) Viral vector-mediated downregulation of RhoA increases survival and axonal regeneration of retinal ganglion cells. Front Cell Neurosci 8:273. doi:10.3389/fncel.2014.00273 pmid:25249936
    OpenUrlCrossRefPubMed
  11. ↵
    1. Koprich JB,
    2. Reske-Nielsen C,
    3. Mithal P,
    4. Isacson O
    (2008) Neuroinflammation mediated by IL-1β increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson's disease. J Neuroinflammation 5:8. doi:10.1186/1742-2094-5-8 pmid:18304357
    OpenUrlCrossRefPubMed
  12. ↵
    1. Korecka JA,
    2. Moloney EB,
    3. Eggers R,
    4. Hobo B,
    5. Scheffer S,
    6. Ras-Verloop N,
    7. Pasterkamp RJ,
    8. Swaab DF,
    9. Smit AB,
    10. van Kesteren RE,
    11. Bossers K,
    12. Verhaagen J
    (2017) Repulsive guidance molecule a (RGMa) induces neuropathological and behavioral changes that closely resemble Parkinson's disease. J Neurosci 37:9361–9379. doi:10.1523/JNEUROSCI.0084-17.2017 pmid:28842419
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Malagelada C,
    2. Jin ZH,
    3. Greene LA
    (2008) RTP801 is induced in Parkinson's disease and mediates neuron death by inhibiting Akt phosphorylation/activation. J Neurosci 28:14363–14371. doi:10.1523/JNEUROSCI.3928-08.2008 pmid:19118169
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Matsunaga E,
    2. Tauszig-Delamasure S,
    3. Monnier PP,
    4. Mueller BK,
    5. Strittmatter SM,
    6. Mehlen P,
    7. Chédotal A
    (2004) RGM and its receptor neogenin regulate neuronal survival. Nat Cell Biol 6:749–755. doi:10.1038/ncb1157 pmid:15258591
    OpenUrlCrossRefPubMed
  15. ↵
    1. Mothe AJ,
    2. Tassew NG,
    3. Shabanzadeh AP,
    4. Penheiro R,
    5. Vigouroux RJ,
    6. Huang L,
    7. Grinnell C,
    8. Cui YF,
    9. Fung E,
    10. Monnier PP,
    11. Mueller BK,
    12. Tator CH
    (2017) RGMa inhibition with human monoclonal antibodies promotes regeneration, plasticity and repair, and attenuates neuropathic pain after spinal cord injury. Sci Rep 7:10529. doi:10.1038/s41598-017-10987-7 pmid:28874746
    OpenUrlCrossRefPubMed
  16. ↵
    1. Semenova MM,
    2. Mäki-Hokkonen AM,
    3. Cao J,
    4. Komarovski V,
    5. Forsberg KM,
    6. Koistinaho M,
    7. Coffey ET,
    8. Courtney MJ
    (2007) Rho mediates calcium-dependent activation of p38alpha and subsequent excitotoxic cell death. Nat Neurosci 10:436–443. doi:10.1038/nn1869 pmid:17369826
    OpenUrlCrossRefPubMed
  17. ↵
    1. Tagliaferro P,
    2. Burke RE
    (2016) Retrograde axonal degeneration in Parkinson disease. J Parkinsons Dis 6:1–15. doi:10.3233/JPD-150769 pmid:27003783
    OpenUrlCrossRefPubMed
  18. ↵
    1. Tanabe S,
    2. Yamashita T
    (2014) Repulsive guidance molecule-a is involved in Th17-cell-induced neurodegeneration in autoimmune encephalomyelitis. Cell Rep 9:1459–1470. doi:10.1016/j.celrep.2014.10.038 pmid:25456136
    OpenUrlCrossRefPubMed
  19. ↵
    1. Tassew NG,
    2. Mothe AJ,
    3. Shabanzadeh AP,
    4. Banerjee P,
    5. Koeberle PD,
    6. Bremner R,
    7. Tator CH,
    8. Monnier PP
    (2014) Modifying lipid rafts promotes regeneration and functional recovery. Cell Rep 8:1146–1159. doi:10.1016/j.celrep.2014.06.014 pmid:25127134
    OpenUrlCrossRefPubMed
  20. ↵
    1. Van Battum EY,
    2. Brignani S,
    3. Pasterkamp RJ
    (2015) Axon guidance proteins in neurological disorders. Lancet Neurol 14:532–546. doi:10.1016/S1474-4422(14)70257-1 pmid:25769423
    OpenUrlCrossRefPubMed
Back to top

In this issue

The Journal of Neuroscience: 38 (6)
Journal of Neuroscience
Vol. 38, Issue 6
7 Feb 2018
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Advertising (PDF)
  • Ed Board (PDF)
Email

Thank you for sharing this Journal of Neuroscience article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
A Repulsive Environment Induces Neurodegeneration of Midbrain Dopaminergic Neurons
(Your Name) has forwarded a page to you from Journal of Neuroscience
(Your Name) thought you would be interested in this article in Journal of Neuroscience.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
View Full Page PDF
Citation Tools
A Repulsive Environment Induces Neurodegeneration of Midbrain Dopaminergic Neurons
Angel J. Santiago-Lopez
Journal of Neuroscience 7 February 2018, 38 (6) 1323-1325; DOI: 10.1523/JNEUROSCI.3070-17.2017

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Respond to this article
Request Permissions
Share
A Repulsive Environment Induces Neurodegeneration of Midbrain Dopaminergic Neurons
Angel J. Santiago-Lopez
Journal of Neuroscience 7 February 2018, 38 (6) 1323-1325; DOI: 10.1523/JNEUROSCI.3070-17.2017
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Footnotes
    • References
  • Info & Metrics
  • eLetters
  • PDF

Responses to this article

Respond to this article

Jump to comment:

No eLetters have been published for this article.

Related Articles

Cited By...

More in this TOC Section

  • Cortical Inhibition, Plasticity, and Sleep
  • Dissociating Hippocampal and Cortical Contributions to Predictive Processing
  • Uncovering the Hippocampal Mechanisms Underpinning Spatial Learning and Flexible Navigation
Show more Journal Club
  • Home
  • Alerts
  • Visit Society for Neuroscience on Facebook
  • Follow Society for Neuroscience on Twitter
  • Follow Society for Neuroscience on LinkedIn
  • Visit Society for Neuroscience on Youtube
  • Follow our RSS feeds

Content

  • Early Release
  • Current Issue
  • Issue Archive
  • Collections

Information

  • For Authors
  • For Advertisers
  • For the Media
  • For Subscribers

About

  • About the Journal
  • Editorial Board
  • Privacy Policy
  • Contact
(JNeurosci logo)
(SfN logo)

Copyright © 2023 by the Society for Neuroscience.
JNeurosci Online ISSN: 1529-2401

The ideas and opinions expressed in JNeurosci do not necessarily reflect those of SfN or the JNeurosci Editorial Board. Publication of an advertisement or other product mention in JNeurosci should not be construed as an endorsement of the manufacturer’s claims. SfN does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of any material contained in JNeurosci.